Ventricular arrhythmias and sudden death are responsible for hundreds of thousands of deaths each year throughout the world. Covering the most recent developments in this field, this leading text serves as a guide to this area of increasing clinical importance, addressing a wide range of topics, including:

• basic mechanisms of ventricular tachycardia and ventricular fibrillation
• clinical syndromes and etiologies
• epidemiology and risk stratification
• pharmacologic therapy
• ablation and surgery
• implantable defibrillators

Ventricular Arrhythmias and Sudden Cardiac Death provides the information that cardiologists, cardiac electrophysiologists, cardiac electrophysiology fellows, scientists, industry, and associated professionals need to know about current and evolving Ventricular Tachyarrhythmia treatment and diagnosis. As the most comprehensive book on this topic, it will serve as the text that this readership will turn to first.

Paul J. Wang, MD
Cardiovascular Medicine, Department of Medicine
Stanford University Medical Center
Stanford, CA, USA

Henry H. Hsia, MD
Cardiovascular Medicine, Department of Medicine
Stanford University Medical Center
Stanford, CA, USA

Amin Al-Ahmad, MD
Cardiovascular Medicine, Department of Medicine
Stanford University Medical Center
Stanford, CA, USA

Paul C. Zei, MD
Cardiovascular Medicine, Department of Medicine
Stanford University Medical Center
Stanford, CA, USA

Ventricular Arrhythmias and Sudden Cardiac Death

Mechanism, Ablation, and Defibrillation

John Wiley & Sons

Copyright © 2008 Blackwell Publishing
All right reserved.
ISBN: 978-1-4051-6114-5

Chapter One

The role of spatial dispersion of repolarization and intramural reentry in inherited and acquired sudden cardiac death syndromes

Charles Antzelevitch

Abstract

The cellular basis for intramural reentry that develops secondary to the development of transmural dispersion of repolarization (TDR) is examined in this review. The hypothesis that amplification of spatial dispersion of repolarization underlies the development of intramural reentry and life-threatening ventricular arrhythmias associated with inherited ion channelopathies is probed. The roles of TDR in the long-QT, short-QT, and Brugada syndromes as well as catecholaminergic polymorphic ventricular tachycardia are critically examined. In the long-QT syndrome, amplification of TDR is generally secondary to preferential prolongation of the action potential duration (APD) of M cells, whereas in the Brugada syndrome, it is due to selective abbreviation of the APD of right ventricular epicardium. Preferential abbreviation of APD of either endocardium or epicardium appears to be responsible for amplification of TDR in the short-QT syndrome. The available data suggest that the long-QT, short-QT, and Brugada syndromes are pathologies with very different phenotypes and etiologies, but which share a common final pathway in causing sudden cardiac death.

Keywords:

long QT syndrome; short QT syndrome; Brugada syndrome; polymorphic ventricular tachycardia; electrophysiology

Inherited sudden cardiac death secondary to the development of life-threatening ventricular arrhythmias have been associated with a variety of ion channelopathies such as the long-QT, short-QT, and Brugada syndromes. Table 1.1 lists the genetic defects thus far identified to be associated with these primary electrical diseases. These ion channel defects have been shown to amplify spatial dispersion of repolarization, in some cases with the assistance of pharmacologic agents that further exaggerate the gain or loss of function of ion channel activity. Before examining these interactions, we will review the basis for intrinsic electrical heterogeneity within the ventricular myocardium.

Intrinsic electrical heterogeneity within the ventricular myocardium

It is now well established that ventricular myocardium is comprised of at least three electrophysiologically as well as functionally distinct cell types: epicardial, M, and endocardial cells. These three principal ventricular myocardial cell types differ with respect to phase 1 and phase 3 repolarization characteristics. Ventricular epicardial and M, but not endocardial, cells generally display a prominent phase 1, due to a large 4-aminopyridine (4-AP)-sensitive transient outward current ([I.sub.to]), giving the action potential either a spike-and-dome or a notched configuration. These regional differences in [I.sub.to] were first suggested on the basis of action potential data and subsequently demonstrated using patch clamp techniques in canine, feline, rabbit, rat, ferret, and human ventricular myocytes.

The magnitude of the action potential notch and corresponding differences in [I.sub.to] have also been shown to be different between right and left ventricular epicardium. Similar interventricular differences in [I.sub.to] have also been described for canine ventricular M cells. This distinction is thought to form the basis for why the Brugada syndrome, a channelopathy-mediated form of sudden death, is a right ventricular disease.

Wang and co-workers reported a larger L-type calcium channel current ([I.sub.Ca]) in canine endocardial versus epicardial ventricular myocytes, although other studies have failed to detect any difference in [I.sub.Ca] among cells isolated from epicardium, M, and endocardial regions of the canine left ventricular wall. Myocytes isolated from the epicardial region of the left ventricular wall of the rabbit show a higher density of cAMP-activated chloride current when compared to endocardial myocytes. [I.sub.to2], initially ascribed to a [K.sup.+] current, is now thought to be caused primarily by the calcium-activated chloride current ([I.sub.Cl(Ca)]); it is thought to also contribute to the action potential notch but it is not known whether this current differs among the three ventricular myocardial cell types.

Characteristics of the M cell

Residing in the deep structures of the ventricular wall between the epicardial and endocardial layers, are M cells and transitional cells. The M cell, masonic midmyocardial Moe cell, discovered in the early 1990s, was named in memory of Gordon K Moe. The hallmark of the M cell is that its action potential can prolong more than that of epicardium or endocardium in response to a slowing of rate or in response to agents that prolong APD (Figure 1.1). Histologically, M cells are similar to epicardial and endocardial cells. Electrophysiologically and pharmacologically, they appear to be a hybrid between Purkinje and ventricular cells. Like Purkinje fibers, M cells show a prominent APD prolongation and develop early afterdepolarizations (EAD) in response to [I.sub.Kr] blockers, whereas epicardium and endocardium do not. Like Purkinje fibers, M cells develop delayed after-depolarizations (DAD) more readily in response to agents that calcium load or overload the cardiac cell. [[alpha].sub.1] Adrenoceptor stimulation produces APD prolongation in Purkinje fibers, but abbreviation in M cells, and little or no change in endocardium and epicardium.

Although transitional cells are found throughout much of the wall in the canine left ventricle, M cells displaying the longest action potentials (at basic cycle lengths (BCLs) [greater than or equal to] 2000 ms) are often localized in the deep subendocardium to midmyocardium in the anterior wall, deep subepicardium to midmyocardium in the lateral wall, and throughout the wall in the region of the right ventricular (RV) outflow tracts. M cells are also present in the deep cell layers of endocardial structures, including papillary muscles, trabeculae, and the interventricular septum. Unlike Purkinje fibers, M cells are not found in discrete bundles or islets although there is evidence that they may be localized in discrete muscle layers. Cells with the characteristics of M cells have been described in the canine, guinea pig, rabbit, pig, and human ventricles.

Isolated myocytes dissociated from discrete layers of the left ventricular wall display APD values that differ by more than 200 milliseconds at relatively slow rates of stimulation. When the cells are in a functional syncytium that comprises the ventricular myocardium, electrotonic interactions among the different cells types lead to reduction of the APD dispersion to 25-55 milliseconds. The transmural increase in APD from epicardium to endocardium is relatively gradual, except between the epicardium and subepicardium where there is often a sharp increase in APD (Figure 1.2). This has been shown to be due to an increase in tissue resistivity in this region, which may be related to the sharp transition in cell orientation in this region as well as to reduced expression of connexin43, which is principally responsible for intracellular communication in ventricular myocardium. Moreover, LeGrice et al. have shown that the density of collagen is heterogeneously distributed across the ventricular wall. A greater density of collagen in the deep subepicardium may also contribute to the resistive barrier in this region of the wall, limiting the degree of electrotonic interaction between myocardial layers. The degree of electrotonic coupling, together with the intrinsic differences APD, contribute to TDR in the ventricular myocardium.

The ionic bases for these features of the M cell include the presence of a smaller slowly activating delayed rectifier current ([I.sub.Ks]), a larger late sodium current (late [I.sub.Na]), and a larger Na-Ca exchange current ([I.sub.Na-Ca]). In the canine heart, the rapidly activating delayed rectifier ([I.sub.Kr]) and the inward rectifier ([I.sub.K1]) currents are similar in the three transmural cell types. Transmural and apico-basal differences in the density of [I.sub.Kr] channels have been described in the ferret heart. [I.sub.Kr] message and channel protein are much larger in the ferret epicardium. [I.sub.Ks] is larger in M cells isolated from the right versus left ventricles of the dog. These ionic distinctions sensitize the M cells to a variety of pharmacological agents. Agents that block the rapidly activating delayed rectifier current ([I.sub.Kr]), [I.sub.Ks], or that increase calcium channel current ([I.sub.Ca]) or late [I.sub.Na], generally produce a much greater prolongation of the APD of the M cell than of epicardial or endocardial cells leading to amplification of TDR.

Amplification of transmural heterogeneities normally present in the early and late phases of the action potential can lead to the development of a variety of arrhythmias, including Brugada, long-QT, and short-QT syndromes as well as catecholaminergic ventricular tachycardia (VT).

Brugada syndrome

The Brugada syndrome is an inherited primary electrical disease in which amplification of TDR is believed to lead to the development of polymorphic VT and sudden cardiac death. The Brugada ECG is characterized by an elevated ST segment or J wave appearing in the right precordial leads (V1-V3), often followed by a negative T wave. First described in 1992, the syndrome is associated with a high incidence of sudden cardiac death secondary to a rapid polymorphic VT or ventricular fibrillation (VF). The ECG characteristics of the Brugada syndrome are dynamic and often concealed, but can be unmasked by potent sodium channel blockers such as ajmaline, flecainide, procainamide, disopyramide, propafenone, and pilsicainide.

The Brugada syndrome (BrS) is associated with mutations in SCN5A, the gene that encodes the subunit of the cardiac sodium channel, in approximately 15% of probands. Over one hundred mutations in SCN5A have been linked to the syndrome in recent years (see for references; also see http://www.fsm.it/cardmoc). Only a fraction of these mutations have been studied in expression systems and shown to result in loss of function of sodium channel activity. Weiss et al. described a second locus on chromosome 3, close to but distinct from SCN5A, linked to the syndrome in a large pedigree in which the syndrome is associated with progressive conduction disease, a low sensitivity to procainamide, and a relatively good prognosis. The gene was recently identified in a preliminary report as the Glycerol-3-Phosphate Dehydrogenase 1-Like (GPD1L) gene and the mutation in GPD1L was shown to result in a reduction of [I.sub.Na].

The third and fourth genes associated with the Brugada syndrome were recently identified and shown to encode the [alpha]1 (CACNA1C) and [beta] (CACNB2b) subunits of the L-type cardiac calcium channel. Mutations in the [alpha] and [beta] subunits of the calcium channel also lead to a shorter than normal QT interval, in some cases creating a new clinical entity consisting of a combined Brugada/short-QT syndrome.

Several experimental models of the BrS have been developed using the right coronary-perfused right ventricular wedge preparation. The available data point to amplification of heterogeneities intrinsic to the early phases (phase 1-mediated notch) of the action potential of cells residing in different layers of the right ventricular wall of the heart as the basis for the development of extrasystolic activity and polymorphic VT in BrS (Figure 1.3). Rebalancing of the currents active at the end of phase 1 can lead to accentuation of the action potential notch in right ventricular epicardium, which is responsible for the augmented J wave and ST segment elevation asssociated with the Brugada syndrome (see for references). Under physiologic conditions, the ST segment is isoelectric due to the absence of major transmural voltage gradients at the level of the action potential plateau. Accentuation of the right ventricular action potential notch under pathophysiological conditions leads to exaggeration of transmural voltage gradients and thus to accentuation of the J wave or to an elevation of the J point (Figure 1.3). If the epicardial action potential continues to repolarize before that of endocardium, the T wave remains positive, giving rise to a saddleback configuration of the ST segment elevation. Further accentuation of the notch is accompanied by a prolongation of the epicardial action potential causing it to repolarize after endocardium, thus leading to inversion of the T wave. Despite the appearance of a typical Brugada ECG, accentuation of the RV epicardial action potential (AP) notch alone does not give rise to an arrhythmogenic substrate. The arrhythmogenic substrate may develop with a further shift in the balance of current leading to loss of the action potential dome at some epicardial sites but not others. A steep gradient of TDR develops as a consequence, creating a vulnerable window, which when captured by a premature extrasystole can trigger a reentrant arrhythmia. Because loss of the action potential dome in epicardium is generally heterogeneous, epicardial dispersion of repolarization develops as well. Propagation of the action potential dome from sites at which it is maintained to sites at which it is lost causes local reexcitation via phase 2 reentry, leading to the development of a closely coupled extrasystole capable of capturing the vulnerable window across the ventricular wall, thus triggering a circus movement reentry in the form of VT/VF (Figures 1.3 and 1.4). The polymorphic VT may start in epicardium reentry, but quickly shifts to an intramural reentry before self-terminating or deteriorating to VF.

Evidence in support of these hypotheses derives from experiments involving the arterially perfused right ventricular wedge preparation and from studies in which monophasic action potential (MAP) electrodes were positioned on the epicardial and endocardial surfaces of the right ventricular outflow tract (RVOT) in patients with the Brugada syndrome.

Long-QT syndrome

The long-QT syndromes (LQTS) are phenotypically and genotypically diverse, but have in common the appearance of a long QT interval in the ECG, an atypical polymorphic VT known as Torsade de Pointes (TdP), and, in many but not all cases, a relatively high risk for sudden cardiac death. Ten genotypes of the congenital LQTS have been identified. The identified syndromes are distinguished by mutations in at least eight different ion channel genes, a structural anchoring protein, and a caveolin protein located on chromosomes 3, 4, 6, 7, 11, 17, and 21 (Table 1.1).

The most recent genes associated with LQTS are CAV3 which encodes caveolin-3 and SCN4B which encodes [Na.sub.V] B4, an auxiliary subunit of the cardiac sodium channel. Caveolin-3 spans the plasma membrane twice, forming a hairpin structure on the surface, and is the main constituent of caveolae, small invaginations in the plasma membrane. Mutations both in CAV3 and in SCNB4 produce a gain in function in late [I.sub.Na], causing an LQT3-like phenotype.

LQTS shows both autosomal recessive and autosomal dominant patterns of inheritance: (1) a rare autosomal recessive disease associated with deafness (Jervell and Lange-Nielsen), caused by two genes that encode for the slowly activating delayed rectifier potassium channel (KCNQ1 and KCNE1); and (2) a much more common autosomal dominant form known as the Romano-Ward syndrome, caused by mutations in 10 different genes (Table 1.1). Eight of the 10 genes encode cardiac ion channels.

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